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NEUROLOGY Early Decision: How Embryonic Stem Cells Become Fine-tuned BrainsProtein Promotes Neurons by Holding Back Glia When scientists counted some of Albert Einstein's brain cells decades after his death, they found that the genius had no more neurons than a regular Joe. He did, however, appear to have more glia, leaving behind another posthumous puzzle about the source of his intellect. A new report in the Feb. 8 Cell might yield a clue about his glial superabundance.
Mireya Nadal-Vicens, Michael Greenberg, and Yi Sun (l to r) have begun to explain how neural stem cells manage to give rise to successive waves of neurons and astrocytes during cortical development. Photo by Pam Murray Scientific curiosities aside, the paper by Michael Greenberg, HMS professor of neurology at Children's Hospital, begins to explain how the embryonic brain's stem cells decide whether to mature into nerve or glial cells as development proceeds. With postdoc Yi Sun, MD–PhD student Mireya Nadal-Vicens, and others, Greenberg reports that neurogenin, a protein known to nudge stem cells toward turning into neurons, does so by actively inhibiting the cells' ability to become astrocytes, a type of glial cell. The paper presents data suggesting a new molecular function for a member of the basic helix–loop–helix transcription factors, a prominent class of cell-fate proteins. The study also gives researchers trying to develop future therapeutic stem cells a handle on controlling their maturation with more precision. Despite stem cells' much-vaunted potential to repair damaged tissue or even, eventually, repopulate whole organs, scientists working toward these goals currently are grappling with the mundane but nagging problem that neural stem cells cultured in the laboratory much prefer to turn into glial cells. Even when prodded with neuron-promoting growth factors, adult stem cells in particular yield few neurons. About FaceThe Harvard researchers started out wondering how a single cell type—the neural stem cell deep inside the developing cortex—manages to generate successive waves of different cell types in a beautifully orchestrated way. At first the stem cells give rise to neurons that build up the layers of the cortex throughout much of embryonic development. Around birth, they switch to generating mostly astrocytes, the star-shaped support cells nestled between neurons. And later, they turn out the myelin-producing oligodendrocytes."Why do the early precursors make neurons and not glial cells? It was completely unknown how this sequence takes place," said Greenberg. "This paper provides an answer. Neurogenin suppresses the competing astrocytic fate. Early in development, when neurogenin expression is high, you are going to get neurons. Somehow during later development, its level goes down, and it is then that you get glial cells." The study raises the question of what regulates neurogenin itself, and whether scientists can learn to turn its expression on and off at will. Previous work had shown that neurogenin acts as a transcriptional activator, binding to the promotors of neuron-specifying genes and turning them on. Yet this paper shows neurogenin also inhibits gene expression, and it does so independently of its ability to bind DNA. Instead, neurogenin blocks a signal transduction pathway that Greenberg and others had previously shown to be essential for astrocyte development. It requires that the cytoplasmic STAT3 protein be phosphorylated after a growth factor has bound a membrane receptor so that STAT3 can enter the nucleus and activate the astrocyte program. Neurogenin, the scientists found, prevents this phosphorylation (see diagram). In addition, neurogenin interacts with another transcription factor complex—CBP/p300 bound to the protein Smad1. It sequesters the complex from astrocyte-specifying genes and redirects it to a DNA region containing neural-specifying genes. When neurogenin is expressed, it wins out in a competition for CBP/p300 binding. In its absence, CBP/p300 is free to bind STAT proteins and promote glial development. This is the first time a protein–protein interaction that inhibits gene expression was discovered for neurogenin, said Yi. Previously, scientists thought it acted mostly through its DNA binding domain. The CBP/p300 protein is a generalist among transcription factors, a ubiquitous protein needed for the activation of many different genes throughout the organism. Its interaction with neurogenin and STAT proteins is an example of how "specificity factors" cooperate with general factors, and how different pathways intersect, to create a particular outcome, said Greenberg. Recent work by Greenberg's and other laboratories on neuronal stem cell differentiation has focused on the role of extracellular factors. The cytokines CNTF and LIF nudge precursors down the astrocyte lineage, while the growth factors PDGF, NT3, and others promote a neural fate. Following OrdersBut the results were sometimes confusing. For instance, the growth factor BMP turns some stem cells into neurons and others into astrocytes. The present paper explains this discrepancy, showing that stem cells expressing neurogenin respond to BMP by activating neural genes while cells without neurogenin activate glial genes—suggesting that the inner workings of a cell orchestrate its reaction to a given external factor.By giving scientists a better understanding of the intrinsic controls of cell fate, this work represents a step toward generating more neurons in applied stem cell studies, said Greenberg. Yet once a stem cell is committed to becoming a neuron, it must choose which type it will be, and scientists know even less about how to control this next level of differentiation, he added. On the lighter side, some may be pondering the relative contributions of the brain's executives (read neurons) versus its support staff (the glial cells) to Einstein's stellar mind. Ironically, Greenberg might view the man's abundance of glia as a relative inability of his neurogenin to keep proper tabs on the glial cell numbers. —Gabrielle Strobel |
